Impact of the Commercialization of Three Generic Angiotensin II Receptor Blockers on Adverse Events in Quebec, Canada - A Population-Based Time Series Analysis

Background

Generic and brand-name drugs are assumed to be clinically equivalent and are used interchangeably once approved by health authorities. Most of population-based, time series analyses support generics commercialization, but they are only evaluating prescription rates or economical outcomes [1-3]. Whether bioequivalence of generic drugs translates into clinical equivalence at a population level is unclear.

In this study, the entry of the generic ARB analogs in the Canadian market was characterized, and the impact of generic ARBs commercialization on adverse events was evaluated, in elderly patients in real-life conditions.

The data of this observational retrospective interrupted time series study was retrieved from the Quebec Integrated Chronic Disease Surveillance System (QICDSS) [4]. The 3 brand-name ARBs losartan, valsartan, and candesartan, as well as 16 generic analogs were studied in all dosages. The interrupted time series were constituted of all patients (N=136 177), aged ≥66 years old, who were observed every month for adverse events, namely ER consultations and hospitalizations, 24 months before and 12 months after generics commercialization.

Main results

Approximately 60 % of losartan, valsartan, and candesartan users were women, on average 76-77 years old with ≥3 CV comorbidities for more than a third of patients.

The month when ARB generics were commercialized, the observed rates of adverse events for losartan per 1000 person-months at risk were 114 for generic versus 104 for brand-name users, for valsartan it was 133 for generic users versus 98 for brand-name users, and for candesartan it was 143 for generic users versus 94 for brand-name users.

The interrupted time series analysis revealed an 8.0% increase of adverse events for generic users right after generics commercialization versus stability for losartan brand-name users (0.5%), resulting in a difference of 7.5% (95% CI: −0.9% to 15.9; P=0.0643). For valsartan it was a 11.7% increase of adverse events for generic users right after generic commercialization versus a decrease for brand-name users (−5.4%, resulting in a difference of 17.1%; 95% CI: 9.9%–24.3%; P<0.0001), whereas for candesartan it was a 14.0% increase of adverse events for generic users right after generic commercialization versus a modest decrease for brand-name users (−2.6%, resulting in a difference of 16.6%; 95% CI: 7.9%–25.3%; P<0.0001).

Results from the falsification analysis revealed consistent differences in rates of specific CV outcomes between generic and brand-name users and no difference in rates of nonspecific CV outcomes for losartan and candesartan.

There was an increased rate of nonspecific CV outcomes for early generic valsartan users, which resulted in a non-statistically significant difference issued from the segmented regression model (month of generic valsartan commercialization: 9.1%; 95% CI: −14.2% to 32.4%; P=0.42; ≤1 year later: 0.6%; 95% CI: −25.6% to 26.9%; P=0.8).

Conclusion

The use of generic ARBs resulted in higher rates of hospitalizations and emergency room consultations compared with branded ARBs. The difference was most pronounced in the first month and with candesartan. These findings suggest that there is a need for more accurate pharmacovigilance reporting of generic and brand-name drugs in real-life conditions.

Editorial comment

In his editorial article, Alter sets the scene first with the following observation: ‘Although manufacturers must prove that generic analogues are bioequivalent to their brand-name comparators, the validity of generic drug substitution policies and their investment returns rest on the assumption that such drugs are clinically interchangeable. The extent to which such assumptions have been tested and proven remains unclear.’

Subsequently he discusses the limitations of the study published by Leclerc et al, including:

the study design, which did not incorporate risk-adjustment methodology

the reasons for the increased emergency room visits and hospitalizations linked to generic drugs, which were not investigated

the adverse events associated with generic drugs, which may have occurred with the branded drugs as well

a selection bias, which is possible for those who received generic drugs

The author concludes: ‘If we are to continue to promote drug surveillance research, we may be leaving ourselves vulnerable to having to address clinical uncertainty when faced with imperfect evidence. Solutions will almost certainly necessitate much broader and more comprehensive collaboration between clinical guideline developers, regulatory bodies, policy makers, and the scientific community—perhaps even a conceptual framework to help us map out our next steps, our priorities, and our action plans may be useful. The investment in time, effort, and resources may not be small but may yield a return on investment that approaches or surpasses those associated with generic drugs themselves.’